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Coronaviruses encode two classes of cysteine proteases, which have narrow substrate specificities and either a chymotrypsin- or papain-like fold. These enzymes mediate the processing of the two precursor polyproteins of the viral replicase and are also thought to modulate host cell functions to facilitate infection. The papain-like protease 1 (PL1pro ) domain is present in nonstructural protein 3 (nsp3) of alphacoronaviruses and subgroup 2a betacoronaviruses. It participates in the proteolytic processing of the N-terminal region of the replicase polyproteins in a manner that varies among different coronaviruses and remains poorly understood. Here we report the first structural and biochemical characterization of a purified coronavirus PL1pro domain, that of transmissible gastroenteritis virus (TGEV). Its tertiary structure is compared with that of severe acute respiratory syndrome (SARS) coronavirus PL2pro , a downstream paralog that is conserved in the nsp3's of all coronaviruses. We identify both conserved and unique structural features likely controlling the interaction of PL1pro with cofactors and substrates, including the tentative mapping of substrate pocket residues. The purified recombinant TGEV PL1pro was shown to cleave a peptide mimicking the cognate nsp2|nsp3 cleavage site. Like its PL2pro paralogs from several coronaviruses, TGEV PL1pro was also found to have deubiquitinating activity in anin vitro cleavage assay, implicating it in counteracting ubiquitin-regulated host cell pathways, likely including innate immune responses. In combination with the prior characterization of PL2pro from other alphacoronaviruses, e.g., human coronaviruses 229E and NL63, our results unequivocally establish that these viruses employ two PLpro s with overlapping specificities toward both viral and cellular substrates.

Papain-Like Protease 1 from Transmissible Gastroenteritis Virus: Crystal Structure and Enzymatic Activity toward Viral and Cellular Substrates